Quinoline Intermediates of Receptor Tyrosine Kinase Inhibitors and the Synthesis Thereof

ABSTRACT

This invention is directed to methods of preparing 4-substituted quinoline compounds as intermediates in the manufacture of receptor tyrosine kinase inhibitors and intermediate compounds used in the methods thereof, wherein the 4-substituted quinoline compound has the following general formula (I): 
     
       
         
         
             
             
         
       
     
     wherein substitutions at LG″, PG, A, G, R 1  and R 4  are set forth in the specification.

This application is a divisional of application Ser. No. 11/036,408,filed Jan. 14, 2005, which claims the benefit of U.S. ProvisionalApplication No. 60/537,329, filed Jan. 16, 2004, the entire contents ofall of the above mentioned applications are incorporated herein byreference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention is directed to methods of preparing 4-substitutedquinoline compounds as intermediates in the manufacture of receptortyrosine kinase inhibitors and intermediate compounds used in themethods thereof.

2. Related Background Art

Protein tyrosine kinases (PTKs) are critical in regulating cell growthand differentiation. One general class of PTK is the receptor tyrosinekinase (RTK). Once activated, usually through the binding of a ligand,an RTK initiates signaling for various activities, such as cell growthand replication.

The RTKs comprise one of the larger families of PTKs and have diversebiological activity. At present, at least nineteen (19) distinctsubfamilies of RTKs have been identified. One such subfamily is the“HER” family of RTKs, which includes epidermal growth factor receptor(EGFR), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4).

Under certain conditions, as a result of either mutation or overexpression, studies have shown that these RTKs can become deregulated;the result of which is uncontrolled cell proliferation which can lead totumor growth and cancer (Wilks, A. F., Adv. Cancer Res., 60, 43 (1993)and Parsons, J. T.; Parsons, S. J., Important Advances in Oncology,DeVita, V. T. Ed., J. B. Lippincott Co., Phila., 3 (1993)). For example,over expression of the receptor kinase product of the ErbB2 oncogene hasbeen associated with human breast and ovarian cancers (Slamon, D. J. etal., Science, 244, 707 (1989) and Science, 235, 177 (1987)).

In addition, deregulation of EGFR kinase has been associated withepidermoid tumors (Reiss, M., et al., Cancer Res., 51, 6254 (1991)),breast tumors (Macias, A. et al., Anticancer Res., 7, 459 (1987)), andtumors involving other major organs (Gullick, W. J., Brit. Med. Bull.,47, 87 (1991)).

These RTKs are known to also be involved in processes crucial to tumorprogression, such as apoptosis, angiogenesis and metastasis.

Therefore, inhibitors of these RTKs have potential therapeutic value forthe treatment of cancer and other diseases characterized by uncontrolledor abnormal cell growth. Accordingly, many recent studies have dealtwith the development of specific RTK inhibitors as potential anti-cancertherapeutic agents (e.g., Traxler, P., Exp. Opin. Ther. Patents, 8, 1599(1998) and Bridges, A. J., Emerging Drugs, 3, 279 (1998)).

Quinoline derivatives are known to be important intermediate compoundsin the synthesis of RTK inhibitors. For example, in the following USpatents, quinoline derivatives are disclosed and the compounds arestated to be involved in inhibiting PTK activity: U.S. Pat. Nos.6,288,082 (Sep. 11, 2001) and 6,297,258 (Oct. 2, 2001).

In addition, various methods for the preparation of quinolinederivatives are known in the art, but these methods contain seriouslimitations. One such method is the thermal cyclization reaction.(Sabnis, R. W., et al., J. Hetero. Chem., 29, 65 (1992); Mehta, N. C.,et al., J. Ind. Chem. Soc., 55(2), 193 (1978); Bredereck, H., et al.,Chem. Ber., 98(4), 1081 (1965); Salon, J., et al., fur Chem., 131, 293(2000)). Although commonly used, this method requires high temperatureconditions, which limits its use for large-scale production of quinolinederivatives. This method also requires high dilution conditions, whichresults in an overall decrease in throughput. Furthermore, the yieldsfrom thermal cyclization reactions are typically 50% or less.

Another limitation is that many reactions used in preparing quinolinederivatives often generate unwanted by-products. For example, thechlorination reaction used in preparing quinoline derivatives suffersfrom the generation of viscous tars and decomposition products that aredifficult to clean and remover, which results in yields that varywidely, typically in the range from 24-64%.

Recently, there has been research into other methods for the preparationof quinoline derivatives. One such method involves the use ofmicrowave-assisted methodology for the preparation of quinolones fromaromatic amines. (Dave, C. G., et al., Ind. J. Chem., 41B, 650 (2002)).However, these newer methods also suffer from the same foregoinglimitations, such as the high temperature conditions requirement.

Accordingly, there continues to be a need for novel quinoline compoundsused in the preparation of RTK inhibitors and methods of preparing suchquinoline compounds without the foregoing limitations. In particular,there is a need for methods of preparing such quinoline compoundswithout the requirement of high temperature conditions.

SUMMARY OF THE INVENTION

This invention relates to methods of preparing 4-substituted quinolinecompounds as intermediates in the manufacture of RTK inhibitors andintermediates used in the methods thereof.

Thus, in one aspect, the present invention is a method of preparing a4-substituted quinoline compound comprising the step of reacting acompound of formula (II):

with a reagent of formula POLG′₃, wherein LG′ is halo, to provide acompound of formula (I):

wherein LG is a leaving group selected from the group consisting ofmorpholine, o-mesyl, o-tosyl, trifilate, LG″ is a leaving group selectedfrom the group consisting of morpholine, o-mesyl, o-tosyl, trifilate, orhalogen; PG is a protecting group selected from the group consisting ofacyl, CH₃OC(O)—, EtOC(O)—, Fmoc, trifluoroacetamide, Troc, Phenoc,benzamide, Teoc and cyclic imides such as pthalimide, maleimide and2,5-dimethylpyrrole; A is O, NR, or S, R is H, alkyl, alkenyl oralkynyl; and G, R₁ and R₄ are each, independently, hydrogen, halogen,alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6carbon atoms, alkenyloxy of 2-6 carbon atoms, alkynyloxy of 2-6 carbonatoms, hydroxymethyl, halomethyl, alkanoyloxy of 1-6 carbon atoms,alkenoyloxy of 3-8 carbon atoms, alkynoyloxy of 3-8 carbon atoms,alkanoyloxymethyl of 2-7 carbon atoms, alkenoyloxymethyl of 4-9 carbonatoms, alkynoyloxymethyl of 4-9 carbon atoms, alkoxymethyl of 2-7 carbonatoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms,alkylsulphinyl of 1-6 carbon atoms, alkylsulphonyl of 1-6 carbon atoms,alkylsulfonamido of 1-6 carbon atoms, alkenylsulfonamido of 2-6 carbonatoms, alkynylsulfonamido of 2-6 carbon atoms, hydroxy, trifluoromethyl,trifluoromethoxy, cyano, nitro, carboxy, carboalkoxy of 2-7 carbonatoms, carboalkyl of 2-7 carbon atoms, phenoxy, phthalimide, phenyl,thiophenoxy, benzyl, amino, hydroxyamino, alkoxyamino of 1-4 carbonatoms, alkylamino of 1-6 carbon atoms, dialkylamino of 2 to 12 carbonatoms, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of4 to 12 carbon atoms, N,N-dialkenylamino of 6-12 carbon atoms,phenylamino, benzylamino,

R₇—(C(R₆)₂)_(g)—Y—, R₇—(C(R₆)₂)_(p)-M-(C(R₆)₂)_(k)—Y—, orHet-(C(R₆)₂)_(q)W—(C(R₆)₂—Y—;

or R₁ and R₄ are as defined above and G is R₂—NH—;

or if any of the substituents R₁, R₄ or G are located on contiguouscarbon atoms then they may be taken together as the divalent radical—O—C(R₆)₂—O;

Y is a divalent radical selected from the group consisting of

—(CH₂)_(a)—, —O—, and

R₇ is —NR₆R₆, —OR₆, -J, —N(R₆)₃ ⁺, or —NR₆(OR₆);

M is >NR₆, —O—, >N—(C(R₆)₂)_(p)NR₆R₆, or >N—(C(R₆)₂)_(p)—OR₆;

W is >NR6, —O— or is a bond;

Het is selected from the group consisting of morpholine, thiomorpholine,thiomorpholine S-oxide, thiomorpholine S,S-dioxide, piperidine,pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole,1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan,thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane,tetrahydropyran, and

wherein Het is optionally mono- or di-substituted on carbon or nitrogenwith R₆, optionally mono- or di-substituted on carbon with hydroxy,—N(R₆)₂, or —OR₆, optionally mono or di-substituted on carbon with themono-valent radicals —C(R₆)₂)_(s)OR₆ or —(C(R₆)₂)_(s)N(R₆)₂, andoptionally mono or di-substituted on a saturated carbon with divalentradicals —O— or —O(C(R₆)₂)_(s)O—;

R₆ is hydrogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms,alkynyl of 2-6 carbon atoms, cycloalkyl of 1-6 carbon atoms, carboalkylof 2-7 carbon atoms, carboxyalkyl (2-7 carbon atoms), phenyl, or phenyloptionally substituted with one or more halogen, alkoxy of 1-6 carbonatoms, trifluoromethyl, amino, alkylamino of 1-3 carbon atoms,dialkylamino of 2-6 carbon atoms, nitro, cyano, azido, halomethyl,alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms,alkylthio of 1-6 carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl,phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms, or alkyl of1-6 carbon atoms; with the proviso that the alkenyl or alkynyl moiety isbound to a nitrogen or oxygen atom through a saturated carbon atom;

R₂, is selected from the group consisting of

R₃ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy,carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,

R₇—(C(R₆)₂)_(p)-M-(C(R₆)₂)_(r)—, R₈R₉—CH—

M-(C(R₆)₂)_(r)—, or

Het-C(R₆)₂)_(q)—W—(C(R₆)₂)_(r)—;

R₅ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy,carboalkoxy of 1-6 carbon atoms, phenyl carboalkyl of 2-7 carbon atoms,

R₇—(C(R₆)₂)s—,

R₇—(C(R₆)₂)_(p)-M-(C(R₆)₂)_(r)—, R₈R₉—CH—

M-(C(R₆)₂)_(r)—, or

Het-(C(R₆)₂)_(q)—W—(C(R₆)₂)_(r)—;

R₈, and R₉ are each independently —(C(R₆)₂)_(r)NR₆R₆, or—(C(R₆)₂)_(r)OR₆;

J is independently hydrogen, chlorine, fluorine, or bromine;

Q is an alkyl of 1-6 carbon atoms or hydrogen;

a=0 or 1;

g=1-6;

k=0-4;

n is 0-1;

m is 0-3;

p=2-4;

q=0-4;

r=1-4;

s=1-6;

u=0-4 and v=0-4, wherein the sum of u+v is 2-4;

x=0-3;

y=0-1;

z=0-3;

or a salt thereof.

The present invention is also directed to a method of synthesizing acompound of formula (VIII):

comprising the steps of:

a. reacting a compound of formula (I):

with a nucleophilic reagent of formula HZ-(CH₂)_(n)—X; or

b(i). reacting a compound of formula (II):

with a nucleophilic reagent of formula HZ-(CH₂)_(n)—X to form a compoundof formula (IX):

b(ii). cyclizing the compound of formula (IX) with a reagent of formulaPOLG′ to produce the compound of formula (VIII).

wherein LG, LG′, LG″, PG, A, G, R₁ and R₄ are as defined above, and Zcan be NR, O or S, n is 0 or 1, and X can be cycloalkyl of 3 to 7 carbonatoms, which may be optionally substituted with one or more alkyl of 1to 6 carbon atom groups, or is a pyridinyl, pyrimidinyl, or phenyl ring,wherein the pyridinyl, pyrimidinyl, or phenyl ring may be optionallymono-, di-, or tri-substituted with a substituent selected from thegroup consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro,carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbonatoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylaminoof 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino,benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, andbenzoylamino, or X can be a bicyclic aryl or bicyclic heteroaryl ringsystem of 8 to 12 atoms, where the bicyclic heteroaryl ring contains 1to 4 heteroatoms selected from N, O, and S with the proviso that thebicyclic heteroaryl ring does not contain O—O, S—S, or S—O bonds andwhere the bicyclic aryl or bicyclic heteroaryl ring may be optionallymono- di-, tri, or tetra-substituted with a substituent selected fromthe group consisting of halogen, oxo, thio, alkyl of 1-6 carbon atoms,alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms, azido,hydroxyalkyl of 1-6 carbon atoms, halomethyl, alkoxymethyl of 2-7 carbonatoms, alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbonatoms, alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano,nitro, carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7carbon atoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino,alkylamino of 1-6 carbon atoms, dialkyl amino of 2 to 12 carbon atoms,phenylamino, benzylamino, alkanoylamino of 1-6 carbon atoms,alkenoylamino of 3-8 carbon atoms, alkynoylamino of 3-8 carbon atoms,carboxyalkyl of 2-7 carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms,aminoalkyl of 1-5 carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, andbenzoylamino, or X can be a radical having the formula:

wherein A′ is a pyridinyl, pyrimidinyl, or phenyl ring; wherein thepyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- ordi-substituted with a substituent selected from the group consisting ofhalogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynylof 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms,halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms,hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl,thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms,carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms,N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms,N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino,T is bonded to a carbon of A′ and is:

—NH(CH₂)_(m)—, —O(CH₂)_(m)—, —S(CH₂)_(m)—, —NR(CH₂)_(m)—,

—(CH₂)_(m)——(CH₂)_(m)NH—, —(CH₂)_(m)O—, —CH₂)_(m)S—, or

—(CH₂)_(m)NR—, and L is an unsubstituted phenyl ring or a phenyl ringmono-, di-, or tri-substituted with a substituent selected from thegroup consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro,carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbonatoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylaminoof 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino,benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, andbenzoylamino, or L can be a 5- or 6-membered heteroaryl ring where theheteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S,with the proviso that the heteroaryl ring does not contain O—O, S—S, orS—O bonds, and where the heteroaryl ring is optionally mono- ordi-substituted with a substituent selected from the group consisting ofhalogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbonatoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbonatoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethylof 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbonatoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl,thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms,carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms,N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms,N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino.

In another aspect, the present invention is an intermediatearyl-2-propenamide compound used in the foregoing method of preparing a4-substituted quinoline compound of formula (I), the aryl-2-propenamidecompound having the following formula (II):

wherein LG, PG, A, G, R₁ and R₄ are as defined above.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formulas (I), (II) and (VIII) can be readily preparedaccording to the following reaction schemes or modification thereof. Inthe following reaction schemes LG, LG′, LG″, X, PG, A, G, R₁, and R₄ areselected from the groups defined above.

Scheme 1 illustrates preferred embodiments of the method of preparing a4-substituted quinoline compound.

In Scheme 1, LG, LG′, LG″, PG, A, G, R₁ and R₄ are as defined above.

The quinoline compounds of the present invention have a protecting group(PG) selected from the group consisting of acyl, CH₃OC(O)—, EtOC(O)—,Fmoc, trifluoroacetamide, Troc, Phenoc, benzamide, Teoc and cyclicimides such as pthalimide, maleimide and 2,5-dimethylpyrrole at thesubstituted A attached to the 6-position of the quinoline ring system.

The method of preparing quinoline compounds of the present invention hasmultiple distinct advantages over previous methods of preparingquinoline core compounds. Most significantly, a high temperature (e.g.,250° C.) cyclization step is not required for the present method. Inaddition, the present method generates little or no insoluble andviscous tars; and the formation of decomposition products is minimized.Furthermore, the current method reduces the number of steps required toprepare the desired quinoline compounds.

The method depicted in Scheme 1 shows that compound of formula (II) canbe converted to a compound of formula (I) via formation of intermediate(VII). However, the intermediate of formula (VII) can also be isolated.Therefore, this method allows a quinoline compound to be formed with avariety of leaving groups at the 4-position. These quinoline compoundscan then be further substituted by reacting them with a nucleophilicreagent.

With these advantages, the present method overcomes many of thelimitations of previous methods, resulting in higher throughput and amore cost-effective way to prepare quinoline core compounds for use inthe manufacture of RTK inhibitors.

In a preferred embodiment, the compounds of formula (I), (II) and (VIII)are subject to the following provisos:

When R₆ is an alkenyl of 2-7 carbon atoms or alkynyl of 2-7 carbonatoms, such alkenyl or alkynyl moiety is bound to a nitrogen or oxygenatom through a saturated carbon atom.

Further, when Y is —NR₆— and R₇ is —NR₆R₆, —N(R₆)₃ ⁺, or —NR₆(OR₆), theng=2-6; when M is —O— and R₇ is —OR₆ then p=1-4; when Y is —NR₆— thenk=2-4; when Y is —O— and M or W is —O— then k=1-4; when W is not a bondwith Het bonded through a nitrogen atom then q=2-4; and when W is a bondwith Het bonded through a nitrogen atom and Y is —O— or —NR₆— thenk=2-4.

For purposes of this invention the term “alkyl” includes both straightand branched alkyl moieties, which can contain as many as 12 carbonatoms. Preferably, the alkyl moiety contains between 1 to 6 carbonatoms, though 1 to 4 carbon atoms is more preferable. The term “alkenyl”refers to a radical aliphatic hydrocarbon containing one double bond andincludes both straight and branched alkenyl moieties of 2 to 6 carbonatoms. Such alkenyl moieties may exist in the E or Z configurations; thecompounds of this invention include both configurations. The term“alkynyl” includes both straight chain and branched moieties containing2 to 6 carbon atoms having at least one triple bond. The term“cycloalkyl” refers to alicyclic hydrocarbon groups having 3 to 12carbon atoms and includes but is not limited to: cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, oradamantyl.

For purposes of this invention the term “aryl” is defined as an aromatichydrocarbon moiety and may be substituted or unsubstituted. An arylgroup preferably contains 6 to 12 carbon atoms and may be selected from,but not limited to, the group: phenyl, α-naphthyl, β-naphthyl, biphenyl,anthryl, tetrahydronaphthyl, phenanthryl, fluorenyl, indanyl,biphenylenyl, acenaphthenyl, acenaphthylenyl, or phenanthrenyl groups.An aryl group may be optionally mono-, di-, tri- or tetra-substitutedwith substituents selected from, but not limited to, the groupconsisting of alkyl, acyl, alkoxycarbonyl, alkoxy, alkoxyalkyl,alkoxyalkoxy, cyano, halogen, hydroxy, nitro, trifluoromethyl,trifluoromethoxy, trifluoropropyl, amino, alkylamino, dialkylamino,dialkylaminoalkyl, hydroxyalkyl, alkoxyalkyl, alkylthio, —SO₃H, —SO₂NH₂,—SO₂NHalkyl, —SO₂N(alkyl)₂, —CO₂H, CO₂NH₂, CO₂NHalkyl, and—CO₂N(alkyl)₂. Preferred substituents for aryl and heteroaryl include:alkyl, halogen, amino, alkylamino, dialkylamino, trifluoromethyl,trifluoromethoxy, arylalkyl, and alkylaryl.

For purposes of this invention the term “heteroaryl” is defined as anaromatic heterocyclic ring system (monocyclic or bicyclic) where theheteroaryl moieties are five or six membered rings containing 1 to 4heteroatoms selected from the group consisting of S, N, and O, andinclude but is not limited to: (1) furan, thiophene, indole, azaindole,oxazole, thiazole, isoxazole, isothiazole, imidazole, N-methylimidazole,pyridine, pyrimidine, pyrazine, pyrrole, N-methylpyrrole, pyrazole,N-methylpyrazole, 1,3,4-oxadiazole, 1,2,4-triazole,1-methyl-1,2,4-triazole, 1H-tetrazole, 1-methyltetrazole, benzoxazole,benzothiazole, benzofuran, benzisoxazole, benzimidazole,N-methylbenzimidazole, azabenzimidazole, indazole, quinazoline,quinoline, pyrrolidinyl; (2) a bicyclic aromatic heterocycle where aphenyl, pyridine, pyrimidine or pyridizine ring is: (i) fused to a6-membered aromatic (unsaturated) heterocyclic ring having one nitrogenatom; (ii) fused to a 5 or 6-membered aromatic (unsaturated)heterocyclic ring having two nitrogen atoms; (iii) fused to a 5-memberedaromatic (unsaturated) heterocyclic ring having one nitrogen atomtogether with either one oxygen or one sulfur atom; or (iv) fused to a5-membered aromatic (unsaturated) heterocyclic ring having oneheteroatom selected from O, N or S. Preferably a bicyclic heteroarylgroup contains 8 to 12 carbon atoms.

For the purposes of this invention the term “alkoxy” is defined asC₁-C₆-alkyl-O—; wherein alkyl is as defined above.

For purposes of this invention the term “alkanoyloxymethyl” is definedas —CH₂OC(O)R, wherein R is alkyl of 1 to 6 carbon atoms.

The terms “alkylaminoalkoxy” and “dialkylaminoalkoxy” refer toalkylamino and dialkylamino moieties with one or two alkyl groups (thesame or different) bonded to the nitrogen atom which is attached to analkoxy group of 1 to 6 carbon atoms. Preferably a dialkylaminoalkoxymoiety consist of 3 to 10 carbon atoms and a alkylaminoalkoxy moietyconsist of from 2 to 9 carbon atoms.

For purposes of this invention the term “alkylthio” is defined asC₁-C₆-alkyl-S.

For purposes of this invention “alkoxyalkyl” and “alkylthioalkyl” denotean alkyl group as defined above that is further substituted with analkoxy or alkylthio as defined above. A preferred alkoxyalkyl moiety isalkoxymethyl (e.g. alkoxy-CH₂—).

For purposes of this invention the term “hydroxy” is defined as aHO—moiety. Furthermore, for purposes of this invention the term“hydroxylalkyl” is defined as a HO-alkyl- moiety, wherein the alkylmoiety consist of 1 to 6 carbons.

For purposes of this invention the term “benzoylamino” is defined as aPh-OC(O)NH— moiety.

The terms “monoalkylamino” and “dialkylamino” refer to moieties with oneor two alkyl groups wherein the alkyl chain is 1 to 6 carbons and thegroups may be the same or different. The terms “monoalkylaminoalkyl” and“dialkylaminoalkyl” refer to monoalkylamino and dialkylamino moietieswith one or two alkyl groups (the same or different) bonded to thenitrogen atom which is attached to an alkyl group of 1 to 6 carbonatoms. Preferably a dialkylaminoalkyl moiety consist of 3 to 10 carbonatoms and a alkylaminoalkyl moiety consist of from 2 to 9 carbon atoms.

For purposes of this invention the term “mercapto” is defined as a —SHmoiety.

For purposes of this invention the term “carboxy” is defined as a —COOHmoiety.

For purposes of this invention the term “alkenoylamino” and“alkynoylamino” are defined as a —NH—COOR moiety, wherein R is alkenylor alkynyl of 3 to 8 carbon atoms.

For purposes of this invention the term “carboalkoxy” is defined as—CO₂R, wherein R is alkyl of 1 to 6 carbon atoms.

For purposes of this invention the term “carboalkyl” is defined as —COR,wherein R is alkyl of 1 to 6 carbon atoms.

For purposes of this invention the term “carboxyalkyl” is defined as aHOOCR— moiety, wherein R is alkyl of 1 to 6 carbon atoms.

For purposes of this invention the term “carboalkoxyalkyl” is defined asa —R—CO₂—R′ moiety, wherein R and R′ are alkyl and together consist offrom 2 to 7 carbon atoms.

For purposes of this invention the term “aminoalkyl” is defined asH₂N-alkyl, wherein the alkyl group consist of 1 to 5 carbon atoms.

“Azido” is a radical of the formula —N₃.

For purposes of this invention the term “alkanoylamino” is defined as a—NH—COOR moiety, wherein R is alkyl of 1 to 6 carbon atoms.

“Acyl” is a radical of the formula —(C═O)-alkyl or —(C═O)-perfluoroalkylwherein the alkyl radical or perfluoroalkyl radical is 1 to 6 carbonatoms; preferred examples include but are not limited to, acetyl,propionyl, butyryl, trifluoroacetyl.

For purposes of this invention the term “alkylsulfinyl” is defined as aR′SO— radical, where R′ is an alkyl radical of 1 to 6 carbon atoms.Alkylsulfonyl is a R′SO₂— radical, where R′ is an alkyl radical of 1 to6 carbon atoms. Alkylsulfonamido, alkenylsulfonamido, alkynylsulfonamidoare R′SO₂NH—radicals, where R′ is an alkyl radical of 1 to 6 carbonatoms, an alkenyl radical of 2 to 6 carbon atoms, or an alkynyl radicalof 2 to 6 carbon atoms, respectively.

The term “substituent” is used herein to refer to an atom radical, afunctional group radical or a moiety radical that replaces a hydrogenradical on a molecule. Unless expressly stated otherwise, it should beassumed that any of the substituents may be optionally substituted withone or more groups selected from: alkyl, halogen, haloalkyl,hydroxyalkyl, nitro, amino, hydroxy, cyano, alkylamino, dialkylamino,alkoxy, haloalkoxy, alkoxyalkyl, alkoxyalkoxy, oxo, alkylthio, mercapto,haloalkylthio, aryl, aryloxy, arylthio, heteroaryl, heteroaryloxy,heteroarylthio, acyl, —CO₂-alkyl, —SO₃H, —SO₂NH₂, —SO₂NH-alkyl,—SO₂NH—(alkyl)₂, —CO₂H, —CO₂NH₂, —CO₂NH-alkyl and —CO₂N-(alkyl)₂.

For purposes of this invention, a “halogen” is one of the non-metallicelements found in group VII A of the periodic table. Accordingly, ahalogen of the present invention is a monovalent moiety which is derivedfrom fluorine, chlorine, bromine, iodine or astatine. Preferred halogensare selected from the group consisting of chloro, fluoro and bromo.

For the purposes of this invention the term “substituted” refers towhere a hydrogen radical on a molecule has been replaced by another atomradical, a functional group radical or a moiety radical; these radicalsbeing generally referred to as “substituents.”

For purposes of this invention, the term “protecting group” refers to agroup introduced into a molecule to protect a sensitive functional groupor specific position on the molecule from reacting when the molecule isexposed to reagents or conditions to transform or react another part ofthe molecule. Thereafter the protecting group can be removed. Suitableprotecting groups are well known in the art and include acid-labile,base-labile, photoremovable, or removable under neutral conditions. See,e.g., Green, Protecting Groups in Organic Synthesis, Wiley, pp. 218-288(1985), which is incorporated herein by reference.

For the present invention, suitable protecting groups are of acyl,CH₃OC(O)—, EtOC(O)—, Fmoc, trifluoroacetamide, Troc, Phenoc, benzamide,Teoc and cyclic imides such as pthalimide, maleimide and2,5-dimethylpyrrole. In one preferred embodiment, the protecting groupis acyl.

The compounds of this invention may contain an asymmetric carbon atomand may thus give rise to stereoisomers, such as enantiomers anddiastereomers. The stereoisomers of the instant invention are namedaccording to the Cahn-Ingold-Prelog System. While shown without respectto stereochemistry in formulas (I), (II) and (VIII), the presentinvention includes all the individual possible stereoisomers; as well asthe racemic mixtures and other mixtures of R and S stereoisomers(scalemic mixtures which are mixtures of unequal amounts of enantiomers)salts thereof. It should be noted that stereoisomers of the inventionhaving the same relative configuration at a chiral center maynevertheless have different R and S designations depending on thesubstitution at the indicated chiral center.

The foregoing method also includes the preparation and forming of saltsof the compounds of formulas (I), (II) and (VIII). As a base, quinolinecan form various acid salts. The salts of the compounds of formulas (I),(II) and (VIII) may be readily prepared by methods known to thosepersons of ordinary skill in the art. For the purpose of this invention,salts are those derived from organic and inorganic acids. Such organicand inorganic acids may be acetic, lactic, citric, tartaric, succinic,maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric,nitric, sulfuric, methanesulfonic, and similarly known acceptable acids.Common mineral acids are HCl, HSO and HNO₃. These lists are intendedonly to provide examples and are not intended to be exhaustive. Thus,the present invention should not be viewed as limited to these examples.

General Synthesis

Scheme 1 illustrates, in part, the synthesis of a 4-substitutedquinoline compound of formula (I) from the starting protectedaryl-2-propenamide compound of formula (II).

As shown in Scheme 1, an aryl-2-propenamide compound of formula (II) istreated with a phosphoryl halide through a Bischler-Napieralskireaction, which results in a compound of formula (I) that is halogenatedat the 4-position. See Bischler, A., Napieralski, B, Ber., 26, 1903(1893), which is incorporated herein by reference, for a generaldescription of the Bischler-Napieralski reaction. However, theintermediate compound of formula (VII) can also be isolated, allowingfor the synthesis of a quinoline with either a morpholine, a mesylate, atosylate, or a trifilate moiety at the 4-position.

These protected anilinoquinoline can be further reacted to form a4-substituted quinoline in the presence of a catalytic amount of acid,such as methylsulfonic acid, pyridinium hydrochloride, hydrochloricacid, sulfuric acid or trifluoroacetic acid, and a nucleophilic reagentof formula HZ-(CH₂)_(n)X, wherein Z can be NR, O or S, n is 0 or 1, andX can be cycloalkyl of 3 to 7 carbon atoms, which may be optionallysubstituted with one or more alkyl of 1 to 6 carbon atom groups, or is apyridinyl, pyrimidinyl, or phenyl ring, wherein the pyridinyl,pyrimidinyl, or phenyl ring may be optionally mono-, di-, ortri-substituted with a substituent selected from the group consisting ofhalogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynylof 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms,halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms,hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl,thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms,carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms,N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms,N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino,or X can be a bicyclic aryl or bicyclic heteroaryl ring system of 8 to12 atoms, where the bicyclic heteroaryl ring contains 1 to 4 heteroatomsselected from N, O, and S with the proviso that the bicyclic heteroarylring does not contain O—O, S—S, or S—O bonds and where the bicyclic arylor bicyclic heteroaryl ring may be optionally mono- di-, tri, ortetra-substituted with a substituent selected from the group consistingof halogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbonatoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbonatoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethylof 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbonatoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl,thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms,dialkyl amino of 2 to 12 carbon atoms, phenylamino, benzylamino,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms,carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms,N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms,N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino,or X can be a radical having the formula:

wherein A′ is a pyridinyl, pyrimidinyl, or phenyl ring; wherein thepyridinyl, pyrimidinyl, or phenyl ring may be optionally mono- ordi-substituted with a substituent selected from the group consisting ofhalogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbon atoms, alkynylof 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbon atoms,halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethyl of 2-7carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbon atoms,hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of 2-7carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl,thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms,carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms,N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms,N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino,T is bonded to a carbon of A′ and is:

—NH(CH₂)_(m)—, —O(CH₂)_(m)—, —S(CH₂)_(m)—, —NR(CH₂)_(m),

—(CH₂)_(m)—(CH₂)_(m)NH—, —CH₂)_(m), —(CH₂)_(m)S—, or

—CH₂)_(m)NR—, and L is an unsubstituted phenyl ring or a phenyl ringmono-, di-, or tri-substituted with a substituent selected from thegroup consisting of halogen, alkyl of 1-6 carbon atoms, alkenyl of 2-6carbon atoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6carbon atoms, halomethyl, alkoxymethyl of 2-7 carbon atoms,alkanoyloxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, hydroxy, trifluoromethyl, cyano, nitro,carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbonatoms, phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, amino, alkylaminoof 1-6 carbon atoms, dialkylamino of 2 to 12 carbon atoms, phenylamino,benzylamino, alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8carbon atoms, alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7carbon atoms, carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5carbon atoms, N-alkylaminoalkyl of 2-9 carbon atoms,N,N-dialkylaminoalkyl of 3-10 carbon atoms, N-alkylaminoalkoxy of 2-9carbon atoms, N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, andbenzoylamino, or L can be a 5- or 6-membered heteroaryl ring where theheteroaryl ring contains 1 to 3 heteroatoms selected from N, O, and S,with the proviso that the heteroaryl ring does not contain O—O, S—S, orS-0 bonds, and where the heteroaryl ring is optionally mono- ordi-substituted with a substituent selected from the group consisting ofhalogen, oxo, thio, alkyl of 1-6 carbon atoms, alkenyl of 2-6 carbonatoms, alkynyl of 2-6 carbon atoms, azido, hydroxyalkyl of 1-6 carbonatoms, halomethyl, alkoxymethyl of 2-7 carbon atoms, alkanoyloxymethylof 2-7 carbon atoms, alkoxy of 1-6 carbon atoms, alkylthio of 1-6 carbonatoms, hydroxy, trifluoromethyl, cyano, nitro, carboxy, carboalkoxy of2-7 carbon atoms, carboalkyl of 2-7 carbon atoms, phenoxy, phenyl,thiophenoxy, benzoyl, benzyl, amino, alkylamino of 1-6 carbon atoms,dialkylamino of 2 to 12 carbon atoms, phenylamino, benzylamino,alkanoylamino of 1-6 carbon atoms, alkenoylamino of 3-8 carbon atoms,alkynoylamino of 3-8 carbon atoms, carboxyalkyl of 2-7 carbon atoms,carboalkoxyalkyl of 3-8 carbon atoms, aminoalkyl of 1-5 carbon atoms,N-alkylaminoalkyl of 2-9 carbon atoms, N,N-dialkylaminoalkyl of 3-10carbon atoms, N-alkylaminoalkoxy of 2-9 carbon atoms,N,N-dialkylaminoalkoxy of 3-10 carbon atoms, mercapto, and benzoylamino.

In another preferred embodiment, the phosphoryl halide used in the aboveBischler-Napieralski reaction is phosphoryl chloride.

For purposes of this invention, a leaving group is a labile atom or agroup of atoms that can be charged or uncharged, that departs during asubstitution or displacement reaction. For the foregoing method,suitable leaving groups may be halo, morpholino, o-mesyl, o-tosyl, or atrifilate.

In a preferred embodiment, the leaving group is morpholino.

As shown in Scheme 1, the aryl-2-propenamide compound of formula (II)may be prepared by various reaction pathways, as described in thefollowing Schemes 2 and 3.

Scheme 2 illustrates one pathway to form an aryl-2-propenamide compoundof formula (II) followed by the synthesis of a 4-halogenated quinolinecompound of formula (I).

As shown in Scheme 2, arylamines are reacted with orthoformate toprepare arylformimidates. The arylformimidates are then condensed withactive methylene compounds (e.g., cyanoacetylmorpholine to providearyl-2-propenamides of formula (II). Through a Bischler-Napieralskireaction, treatment of the aryl-2-propenamides with a phosphoryl halide(e.g., phosphoryl chloride) results in 4-halogenated quinolines (e.g.,4-chloroquinolines).

Scheme 3 illustrates a second pathway to form an aryl-2-propenamidecompound of formula (II) followed by the synthesis of a 4-halogenatedquinoline compound of formula (I).

As shown in Scheme 3, active methylene compounds (e.g., cyanoacetylmorpholine) are condensed with orthoformate to produce alkoxymethylenederivative compounds. These alkoxymethylene derivative compounds arefurther reacted with arylamines to give aryl-2-propenamides of formula(II). Through a Bischler-Napieralski reaction, treatment of thearyl-2-propenamides with a phosphoryl halide (e.g., phosphoryl chloride)results in 4-halogenated quinolines (e.g., 4-chloroquinolines).

The following examples are set forth to aid in an understanding of theinvention, and are not intended, and should not be construed, to limitin any way the invention set forth in the claims that follow thereafter.

EXAMPLE 1 Synthesis of 6-acetamido-4-chloro-3-cyano-7-ethoxyquinolinePreparation of 4-cyanoacetylmorpholine

A 4-neck 500 mL flask was charged with morpholine (77.0 g, 0.088 mol).Ethylcyanoacetate (100.0 g, 0.088 mol) was added. After addition, thereaction mixture was stirred. The mixture progressively turned yellow toclear. The mixture was heated to 100 to 110° C. for 3.0 hours. A solidformed after cooling to room temperature. Ethyl acetate (150 ml) andheptanes (300 ml) were added and the mixture stirred for 30 minutes atroom temperature. The solid was filtered to give 95.2 g (71% yield) of4-cyanoacetylmorpholine. ¹H NMR: δ (DMSO-d₆) 4.02 (s, 2H); 3.37 (m, 2H);3.55 (m, 4H); 3.45 (m, 2H).

Preparation of Propenamide

A 4-neck 250 mL flask was charged with 4-cyanoacetylmorpholine (7.21 g,0.047 mol), aniline (10.0 g, 0.051 mol) and IPA (72 mL). The flask wasequipped with an agitator, thermocoupler and N₂ protection. The mixturewas heated to 50-60° C. The first of three portions of triethylorthoformate (7.8 ml) was added. After one hour, the second portion oftriethyl orthoformate (7.8 ml) was added. After another hour, the thirdportion of triethyl orthoformate (7.8 ml) was added. The resultingsolution was held to 80° C. for 21 hours. Brown solids formed aftercooling to room temperature. The solids were filtered, washed with IPA(2×15 mL) and dried to give 8.43 g (51% yield) of the desired compound.¹H NMR: 6 (DMSO-d₆) 10.69 (d, 1H); 8.93 (s, 1H,), 8.30 (d, 1H), 7.82 (d,1H); 6.86 (dd, 1H); 4.13 (q, 2H); 3.61 (m, 8H); 2.07 (s, 3H); 1.37 (t,3H).

Preparation of 6-acetamido-4-chloro-3-cyano-7-ethoxyquinoline

To a 3-necked 50 ml flask equipped with an agitator, temperature probe,condenser and nitrogen protection was charged propenamide (2.0 g, 5.58mmole) and suspended in acetonitrile (16 ml). The mixture was heated to60-65° C. and phosphorus oxychloride (2.57 g, 1.56 ml, 3.0 eq, d=1.645g/ml) was added dropwise over 2 mins. The mixture becomes clear and deepred within 30 mins. The mixture was held for 14 hours and then cooled to0-15° C. Water (5 ml) was added keeping the pot temperature<20° C. ThepH was adjusted to 8-10 using either 8% aqueous potassium carbonate or50% aqueous sodium hydroxide. The mixture can be treated under variousworkup conditions listed below:

1. The organic solvent was removed on a rotary evaporator. Toluene (20ml) is added the mixture stirred for 1 hour at room temperature thenfiltered and washed with water (25 ml) and heptane (2×25 ml). The solidsare dried overnight at 55-60° C. with full vacuum to give crude product.

2. Alternatively, isopropyl acetate (30 ml) was added and the mixturestirred for a minimum of 30 mins. The pH was re-checked to make sure itremained at 8-10. Additional aqueous potassium carbonate may be added ifnecessary. The layers were separated and the organic phase washed withwater (2×30 ml) and brine (30 ml). To the organic phase was added silicagel 60 (30 g) and the mixture stirred for a minimum of 30 mins. Themixture was filtered and washed with isopropyl acetate (30 ml). Theorganic phase was concentrated to dryness to give crude compound. Thisworkup still left small amounts of polar impurities in the product.

1. A method of preparing a 4-substituted quinoline compound comprisingthe step of reacting a compound of the following formula (II):

with a reagent of formula POLG′₃, wherein LG′ is halo, to provide acompound of the following formula (I):

wherein; LG is a leaving group selected from the group consisting ofmorpholino, o-mesyl, o-tosyl, trifilate; LG″ is a leaving group selectedfrom the group consisting of morpholino, o-mesyl, o-tosyl, trifilate andhalogen; PG is a protecting group selected from the group consisting ofacyl, CH₃OC(O)—, EtOC(O)—, Fmoc, trifluoroacetamide, Troc, Phenoc,benzamide, Teoc, pthalimide, maleimide and 2,5-dimethylpyrrole; A is O,NR, or S; R is H, alkyl, alkenyl, or alkynyl; and G, R₁ and R₄ are each,independently, hydrogen, halogen, alkyl of 1-6 carbon atoms, alkenyl of2-6 carbon atoms, alkynyl of 2-6 carbon atoms, alkenyloxy of 2-6 carbonatoms, alkynyloxy of 2-6 carbon atoms, hydroxymethyl, halomethyl,alkanoyloxy of 1-6 carbon atoms, alkenoyloxy of 3-8 carbon atoms,alkynoyloxy of 3-8 carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms,alkenoyloxymethyl of 4-9 carbon atoms, alkynoyloxymethyl of 4-9 carbonatoms, alkoxymethyl of 2-7 carbon atoms, alkoxy of 1-6 carbon atoms,alkylthio of 1-6 carbon atoms, alkylsulphinyl of 1-6 carbon atoms,alkylsulphonyl of 1-6 carbon atoms, alkylsulfonamido of 1-6 carbonatoms, alkenylsulfonamido of 2-6 carbon atoms, alkynylsulfonamido of 2-6carbon atoms, hydroxy, trifluoromethyl, trifluoromethoxy, cyano, nitro,carboxy, carboalkoxy of 2-7 carbon atoms, carboalkyl of 2-7 carbonatoms, phenoxy, phthalimide, phenyl, thiophenoxy, benzyl, amino,hydroxyamino, alkoxyamino of 1-4 carbon atoms, alkylamino of 1-6 carbonatoms, dialkylamino of 2 to 12 carbon atoms, N-alkylcarbamoyl,N,N-dialkylcarbamoyl, N-alkyl-N-alkenylamino of 4 to 12 carbon atoms,N,N-dialkenylamino of 6-12 carbon atoms, phenylamino, benzylamino,

R₇—(C(R₆)₂)_(g)—Y—, R₇—(C(R₆)₂)_(p)-M-(C(R₆)₂)_(k)—Y—, orHet-(C(R₆)₂)_(q)W—(C(R₆)₂—Y—; or R₁ and R₄ are as defined above and G isR₂—NH—; or if any of the substituents R₁, R₄ or G are located oncontiguous carbon atoms then they may be taken together as the divalentradical —O—C(R₆)₂—O; Y is a divalent radical selected from the groupconsisting of —(CH₂)_(a)—, —O—, and

R₇ is —NR6R6, —OR6, -J, —N(R6)3+, or —NR6(OR6); M is >NR6,—O—, >N—(C(R6)2)pNR6R6, or >N—(C(R6)2)p—OR₆; W is >NR6, —O— or is abond; Het is selected from the group consisting of morpholine,thiomorpholine, thiomorpholine S-oxide, thiomorpholine S,S-dioxide,piperidine, pyrrolidine, aziridine, pyridine, imidazole, 1,2,3-triazole,1,2,4-triazole, thiazole, thiazolidine, tetrazole, piperazine, furan,thiophene, tetrahydrothiophene, tetrahydrofuran, dioxane, 1,3-dioxolane,tetrahydropyran, and

wherein Het is optionally mono- or di-substituted on carbon or nitrogenwith R₆, optionally mono- or di-substituted on carbon with hydroxy,—N(R₆)₂, or —OR₆, optionally mono or di-substituted on carbon with themono-valent radicals —(C(R₆)₂)_(s)OR₆ or —(C(R₆)₂)_(s)N(R₆)₂, andoptionally mono or di-substituted on a saturated carbon with divalentradicals —O— or —O(C(R₆)₂)_(s)O—; R₆ is hydrogen, alkyl of 1-6 carbonatoms, alkenyl of 2-6 carbon atoms, alkynyl of 2-6 carbon atoms,cycloalkyl of 1-6 carbon atoms, carboalkyl of 2-7 carbon atoms,carboxyalkyl (2-7 carbon atoms), phenyl, or phenyl optionallysubstituted with one or more halogen, alkoxy of 1-6 carbon atoms,trifluoromethyl, amino, alkylamino of 1-3 carbon atoms, dialkylamino of2-6 carbon atoms, nitro, cyano, azido, halomethyl, alkoxymethyl of 2-7carbon atoms, alkanoyloxymethyl of 2-7 carbon atoms, alkylthio of 1-6carbon atoms, hydroxy, carboxyl, carboalkoxy of 2-7 carbon atoms,phenoxy, phenyl, thiophenoxy, benzoyl, benzyl, phenylamino, benzylamino,alkanoylamino of 1-6 carbon atoms, or alkyl of 1-6 carbon atoms; withthe proviso that the alkenyl or alkynyl moiety is bound to a nitrogen oroxygen atom through a saturated carbon atom; R₂, is selected from thegroup consisting of

R₃ is independently hydrogen, alkyl of 1-6 carbon atoms, carboxy,carboalkoxy of 1-6 carbon atoms, phenyl, carboalkyl of 2-7 carbon atoms,

R₇—(C(R₆)₂)_(s)—, R₇—(C(R₆)₂)_(p)-M-(C(R₆)₂)_(r)—, R₈R₉—CH—M-(C(R₆)₂)_(r)—, or Het-(C(R₆)₂)_(q)—W—(C(R₆)₂)_(r)—; R₅ isindependently hydrogen, alkyl of 1-6 carbon atoms, carboxy, carboalkoxyof 1-6 carbon atoms, phenyl carboalkyl of 2-7 carbon atoms,

R₇—(C(R₆)₂)_(s)—, R₇—(C(R₆)₂)_(p)-M-(C(R₆)₂)_(r), R₈R₉—CH—M-(C(R₆)₂)_(r)—, or Het-(C(R₆)₂)_(q)—W—(C(R₆)₂)_(r)—; R₈, and R₉ areeach independently —(C(R₆)₂)_(r)NR₆R₆, or —(C(R₆)₂)_(r)OR₆; J isindependently hydrogen, chlorine, fluorine, or bromine; Q is an alkyl of1-6 carbon atoms or hydrogen; a=0 or 1; g=1-6; k=0-4; n is 0-1; m is0-3; p=2-4; q=0-4; s=1-6; u=0-4 and v=0-4, wherein the sum of u+v is2-4; x=0-3; y—0-1; z=0-3; or a salt thereof.
 2. The method of claim 1,wherein LG′ is chloro.
 3. The method of claim 1, further comprising thestep of substituting the LG″ group on a compound of formula (I) with anucleophile.
 4. The method of claim 1, further comprising the step offorming the compound of formula (II) by condensing an active methylenecompound of formula (IV):

with an arylformimidate compound of formula (III):

wherein LG, PG, A and G are as previously defined.
 5. The method ofclaim 4, wherein LG is morpholino, PG is acyl, A is amino and G isethoxy.
 6. The method of claim 4, further comprising the step of formingthe arylformimidate by reacting an arylamine of formula (V):

with orthoformate, wherein PG, A and G are as previously defined.
 7. Themethod of claim 6, wherein the arylamine compound isN-(4-amino-2-ethoxyphenyl)acetamide.
 8. The method of claim 6, whereinthe orthoformate is triethyl orthoformate.
 9. The method of claim 1,further comprising the step of forming the compound of formula (II) byreacting an alkoxymethylene compound of formula (VI):

with an arylamine of formula (V):

wherein LG, PG, A and G are as previously defined.
 10. The method ofclaim 9, wherein LG is morpholino, PG is acyl, A is amino and G isethoxy.
 11. The method of claim 9, further comprising the step offorming the alkoxymethylene compound by condensating an active methylenecompound of formula (IV):

with orthoformate, wherein LG is as previously defined.
 12. The methodof claim 11, wherein the active methylene compound ismorpholinocyanoacetate.
 13. The method of claim 11, wherein theorthoformate is triethyl orthoformate.
 14. The method of claim 1,wherein the treatment of the compound of formula (II) with phosphorylchloride occurs at a temperature in the range of 60 to 100° C.
 15. Themethod of claim 1, wherein a compound of the following formula (VII):

is an intermediate formed after the reaction of a compound of formula(II) with POLG′₃, but before the formation of a compound of formula (I),wherein LG, LG′, PG, A, G, R₁ and R₄ are as previously defined.
 16. Themethod of claim 15, wherein LG is morpholino.
 17. The method of claim16, wherein the compound of formula (VII) isN-[3-cyano-7-ethoxy-4-(4-moropholinyl)-6-quinolinyl]acetamide.
 18. Themethod of claim 1, wherein the compound of formula (I) isN-[4-chloro-3-cyano-7-hydroxy-6-quinolinyl]acetamide.
 19. The method ofclaim 1, wherein the compound of formula (II) is morpholinocyanoenamine.20.-25. (canceled)